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BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma.
Langbein, Lauren E; El Hajjar, Rayan; He, Shen; Sementino, Eleonora; Zhong, Zhijiu; Jiang, Wei; Leiby, Benjamin E; Li, Li; Uzzo, Robert G; Testa, Joseph R; Yang, Haifeng.
Afiliación
  • Langbein LE; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
  • El Hajjar R; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
  • He S; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
  • Sementino E; Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, United States.
  • Zhong Z; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.
  • Jiang W; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
  • Leiby BE; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.
  • Li L; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
  • Uzzo RG; Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States.
  • Testa JR; Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, United States.
  • Yang H; Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States. Electronic address: haifeng.yang@jefferson.edu.
Cancer Lett ; 547: 215885, 2022 10 28.
Article en En | MEDLINE | ID: mdl-35995140
BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) activated interferon beta (IFN-ß) expression in a HIF2α-dependent manner. IFN-ß was required for ISGF3 activation and suppressed the growth of Ren-02 tumors in xenografts. BAP1 enhanced the expression of IFN-ß and stimulator of interferon genes (STING), both of which activate ISGF3. Both ISGF3 overexpression and STING agonist treatment increased ISGF3 activity and suppressed BAP1-deficient tumor growth in Ren-02 xenografts. Our results indicate that BAP1 loss reduces type I interferon signaling, and reactivating this pathway may be a novel therapeutic strategy for treating ccRCC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Lett Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Lett Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda